Treatments for neuropathy

ABSTRACT

Small fiber neuropathy is treated or prevented by topically administering to a subject in need thereof topically active quinoline compounds or pharmaceutically acceptable salts thereof under conditions effective to treat or prevent neuropathy in the subject. Glial cell-derived neurotrophic factor (GDNF) receptors are modulated with the subject active quinoline compounds, which may be formulated in topical lotions.

This application claims priority to U.S. Ser. No. 61/028,024, filed Feb.12, 2008 by the same inventors: Gabriel Corfas and Joshua C. Murtie,both of Boston, Mass.

The subject matter of this application was made with support from theNational Institute for Health (NIH) Grant No. NS035884. The U.S.Government has certain rights.

FIELD OF THE INVENTION

This invention relates to methods of treating or preventing small fiberneuropathy.

BACKGROUND OF THE INVENTION

Small fiber neuropathy (SFN) is a disorder characterized by degenerationor dysfunction of small diameter unmyelinated nerve fibers in theperipheral nervous system (1,2). Patients with SFN have sensory defectswith a variety of symptoms, including loss of sensation or chronic pain.Despite its prevalence, the etiology of SFN is poorly understood andthere are currently no effective treatments. Since the initial stages ofSFN commonly involve degeneration of nerve terminals without loss ofneuronal cell bodies (3), we wondered if delivery of therapeutic agentsat the target of innervation, i.e. the skin, would be an effectivenon-invasive approach that could minimize the side effects commonlyobserved with systemic drug delivery methods.

When considering molecules that could be used in this fashion, wefocused on neurotrophic factors, which have been viewed as potentiallyuseful therapeutic agents in the treatment of peripheral neuropathiesbecause they regulate the survival and function of peripheral nervesduring development (4, 5). In addition, decreases in expression ofcertain trophic factors have been observed in multiple models ofperipheral neuropathy (6, 7) suggesting that low levels of these factorsmay be involved in disease etiology. One of these trophic factors, GDNF,is necessary for proper development and survival of small diameterunmyelinated nerve fibers (5, 8). In early postnatal life, a largeproportion of developing unmyelinated nerve fibers switch fromdependence on nerve growth factor (NGF) to dependence on GDNF (5). Thistransition coincides with a gradual decrease in expression of the NGFreceptor (TrkA) with a corresponding increase in the expression of GDNFfamily receptors by dorsal root ganglion sensory neurons (4). Based onthe known roles of the GDNF pathway in peripheral nerve development andfunction and the pattern of expression of GDNF family ligands andreceptors, we decided to test if application of GDNF receptor ligands tothe skin could be used to treat SFN. To address this question, we usedtwo mouse models of SFN arising from different pathogenic processes. Inone model, progressive SFN results from disruption of non-myelinatingSchwann cell (NMSC) function (6). In the other, rapid onset SFN iscaused by treatment with a toxin (resiniferatoxin, RTX) that activatesTRPV1 channels in c-fiber nerve terminals, inducing loss of unmyelinatedfiber nerve terminals in the skin and loss of thermal nociception (9).Here we show that topical delivery of GDNF receptor ligands to affectedskin areas is sufficient to prevent degeneration and maintain sensoryfunction in both types of SFN. In addition, we demonstrate that thenon-peptidyl GFRα1 agonist XIB4035 and related quinolines are capable ofproviding trophic support to peripheral nerves in vivo and thus areuseful therapeutic agents in the treatment of SFN.

Use ofN4-{7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl}-N1,N1-diethyl-pentane-1,4-diamine(XIB4035), also known as7-chloro-2-(o-chlorostyryl)-4-[4diethylamino-1-methylbutyl]aminoquiinolinephosphate), and2-(2-Chlorostyryl)-4-(delta-diethylamino-alpha-methylbutylamino)-7-chloroquinazoline(CAS RN 57942-32-2; CAS 10023-54-8) has been described, e.g. Tokugawa etal., Neurochem Intnl 2003, 42, 81-86; WO01003649; and JP 2008-230974.

SUMMARY OF THE INVENTION

The invention provides methods and compositions for treating orpreventing small fiber peripheral neuropathy in a subject determined tobe in need thereof, and generally comprising: (a) topicallyadministering to the subject an anti-peripheral neuropathic quinolinecompound of the formula:

wherein R₁-R₇ are each independently H, hydroxy, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted aryl alkyl,substituted or un substituted amine, substituted or un substitutedalkylamine, substituted or unsubstituted dialkylamine, substituted orunsubstituted alkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkoxy,substituted or unsubstituted haloalkyl, or a pharmaceutically acceptablesalt thereof, under conditions effective to treat or prevent theperipheral neuropathy in the subject.

In particular embodiments the method further comprises the antecedentstep of determining that the subject is in need thereof, e.g. bydetecting or diagnosing the small fiber neuropathy in the subject orpatient, or that the subject is at particular risk of developing theneuropathy.

In particular embodiments, the method further comprises the subsequentstep of detecting a resultant effect on the subject, such as adiminution in the severity of the neuropathy, or delayed onset of theneuropathy.

The invention encompasses all alternative combinations of particularembodiments:

R₂ is halogen, particularly Cl;R₅ is a substituted amine, particularly optionally-substituted alkylsubstituted secondary amine, particularly wherein the alkyl issubstituted with a dialkylamine such as 1-methyl-3-diethylaminobutyl,1-methyl-4-dimethylaminobutyl, 1-ethyl-4-dimethylaminobutyl,1-ethyl-4-diethylaminobutyl, or 1-methyl-4-diethylaminobutyl:

R₇ is a substituted alkenyl, particularly optionally-substituted phenylsubstituted ethenyl, particularly such as

and/orwherein R₈ is hydrogen or halogen, such as Cl, particularlyortho-chloro:such as wherein the compound has formula:

In another aspect, the invention provides methods and compositions fortreating or preventing a small fiber peripheral neuropathy in a subjectdetermined to be in need thereof, and generally comprising: topicallyadministering to the subject an agonist of glial cell-derivedneurotrophic factor (GDNF) receptor GFRα1 or GFRα2, under conditionseffective to treat or prevent the peripheral neuropathy in the subject,particularly, wherein the agonist is XIB4035.

In another aspect, the invention provides a topical lotion comprising(a) a subject anti-peripheral neuropathic quinoline compound, or apharmaceutically acceptable salt thereof; and (b) a pharmaceuticallyacceptable carrier formulated for topical application.

DESCRIPTION OF PARTICULAR EMBODIMENTS OF THE INVENTION

In one embodiment, the invention provides methods of treating orpreventing small fiber neuropathy in a subject, particularly a human,determined to be in need thereof, the method comprising the step of (a)topically administering to the subject a compound of the formula:

wherein R₁-R₇ are each independently H, hydroxy, halogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted arylalkyl,substituted or unsubstituted amine, substituted or unsubstitutedalkylamine, substituted or unsubstituted dialkylamine, substituted orunsubstituted alkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkoxy,substituted or unsubstituted haloalkyl, or a pharmaceutically acceptablesalts thereof under conditions effective to treat or prevent the smallfiber peripheral neuropathy in the subject.

“Alkyl” as used herein refers to a saturated hydrocarbon radical whichmay be straight-chain or branched-chain (for example, ethyl, isopropyl,t-amyl, or 2,5-dimethylhexyl) or cyclic (for example cyclobutyl,cyclopropyl or cyclopentyl) and contains from 1 to 24 carbon atoms. Thisdefinition applies both when the term is used alone and when it is usedas part of a compound term, such as “haloalkyl” and similar terms. Insome embodiments, preferred alkyl groups are those containing 1 to 4carbon atoms, which are also referred to as “lower alkyl.” In someembodiments preferred alkyl groups are those containing 5 or 6 to 24carbon atoms, which may also be referred to as “higher alkyl”.

“Alkenyl,” as used herein, refers to a straight or branched chainhydrocarbon containing from 2 to 24 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of “alkenyl” include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.“Lower alkenyl” as used herein, is a subset of alkenyl and refers to astraight or branched chain hydrocarbon group containing from 1 to 4carbon atoms.

“Alkynyl,” as used herein, refers to a straight or branched chainhydrocarbon group containing from 2 to 24 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,3-butynyl, 2-pentynyl, 1-butynyl and the like. “Lower alkynyl” as usedherein, is a subset of alkyl and refers to a straight or branched chainhydrocarbon group containing from 1 to 4 carbon atoms.

“Alkoxy” refers to an alkyl radical as described above which also bearsan oxygen substituent which is capable of covalent attachment to anotherhydrocarbon radical (such as, for example, methoxy, ethoxy andt-butoxy).

“Alkylthio” as used herein refers to an alkyl group, as defined herein,appended to the parent molecular moiety through a thio moiety, asdefined herein. Representative examples of alkylthio include, but arenot limited, methylthio, ethylthio, tert-butylthio, hexylthio, and thelike.

“Aryl” or “aromatic ring moiety” refers to an aromatic substituent whichmay be a single ring or multiple rings which are fused together, linkedcovalently or linked to a common group such as an ethylene or methylenemoiety. The aromatic rings may each contain heteroatoms and hence “aryl”encompasses “heteroaryl” as used herein. Representative examples of arylinclude, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl,thienyl, pyridyl and quinoxalyl. “Aryl” means substituted orunsubstituted aryl unless otherwise indicated and hence the arylmoieties may be optionally substituted with halogen atoms, or othergroups such as nitro, carboxyl, alkoxy, phenoxy and the like.Additionally, the aryl radicals may be attached to other moieties at anyposition on the aryl radical which would otherwise be occupied by ahydrogen atom (such as, for example, 2-pyridyl, 3-pyridyl and4-pyridyl).

“Heteroaryl” means a cyclic, aromatic hydrocarbon in which one or morecarbon atoms have been replaced with heteroatoms. If the heteroarylgroup contains more than one heteroatom, the heteroatoms may be the sameor different. Examples of heteroaryl groups include pyridyl,pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl,triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl,quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, is othiazolyl, andbenzo[b]thienyl. Preferred heteroaryl groups are five and six memberedrings and contain from one to three heteroatoms independently selectedfrom 0, N, and S. The heteroaryl group, including each heteroatom, canbe unsubstituted or substituted with from 1 to 4 substituents, aschemically feasible.

“Halo” or “halogen,” as used herein, refers to —Cl, —Br, —I or —F.

“Haloalkyl,” as used herein, refers to at least one halogen, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of haloalkyl include, but arenot limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.

“Hydroxy,” as used herein, refers to an —OH group.

“Amine” or “amino” as used herein, refers to a nitrogen atom attached bysingle bonds to hydrogen atoms, alkyl groups, aryl groups, or acombination of these three. An organic compound that contains an aminogroup is called an amine. Amines are derivatives of the inorganiccompound ammonia, NH₃. When one, two, or all three of the hydrogens inammonia are replaced by an alkyl or aryl group, the resulting compoundis known as a primary, secondary, or tertiary amine, respectively.

In certain embodiments, R₂ may be halogen, R₅ may be a substitutedamine, and/or R₇ may be a substituted alkenyl such as

wherein R₈ may be H or halogen, for example, Cl.

In preferred embodiments, R₂ is Cl, R₅ is

The subject topically-active, anti-peripheral neuropathic quinolinecompounds are commercially available and/or readily produced usingconvention organic synthesis. Relevant derivitization schemes are knownin the art, such as described in “Synthesis of substituted4-(δ-diethylamino-α-methylbutylamino)-2-styrylquinolines”, Berenfel'd,V. M.; Yakhontov, L. N.; Yanbukhtin, N. A.; Krasnokutskaya, D. M.;Vatsenko, S. V.; Rubtsov, M. V. Zhurnal Obshchei Khimii (1962), 322169-77. CODEN: ZOKHA4 ISSN: 0044-460X; “Syntheses in the isoquinolineseries. Hofmann degradation of 1-phenyl-substituted1,2,3,4-tetrahydroisoquinolines,” Rheiner, A., Jr.; Brossi, A. F.Hoffmann-La Roche & Co., A.-G., Basel, Switz. Helvetica Chimica Acta(1962), 45 2590-600. CODEN: HCACAV ISSN: 0018-019X; “Synthesis andantileishmaniasis activity of2-(2′-chlorostyryl)-4-(δ-diethylamino-α-methylbutylamino)-7-chloroquinazolinediphosphate,” Yakhontov, L. N.; Zhikhareva, G. P.; Mastafanova, L. I.;Evstratova, M. I.; Pershin, G. N.; Moskalenko, N. Yu.; Pushkina, T. V.;Kutchak, S. N.; Fadeeva, N. I.; et al. VNIFI, Moscow, USSR.Khimiko-Farmatsevticheskii Zhurnal (1987), 21(1), 38-49. CODEN: KHFZANISSN: 0023-1134; and “Reaction products of4-[[4-(diethylamino)-1-methylbutyl]amino]-7-chloroquinaldine witho-chlorobenzaldehyde,” Uritskaya, M. Ya.; Anisimova, O. S.; Tubina, I.S.; Vinokurova, T. Yu.; Pershin, G. N.; Moskalenko, N. Yu.; Gus'kova, T.A.; Kutchak, S. N.; Stebaeva, L. F. Vses. Nauchno-Issled. Khim.-Farm.Inst., Moscow, USSR. Khimiko-Farmatsevticheskii Zhurnal (1983), 17(11),1334-40. CODEN: KHFZAN ISSN: 0023-1134.

Anti-peripheral neuropathic activity is readily confirmed in topicalformulations and the convenient animal models, as demonstrated below.The subject compounds are topically-active, antineuropathic quinolines,particularly aminoquinolines, particularly 4- and 8-aminoquinolines,particularly chloroquines (chloroquine and derivatives thereof), andinclude compounds of Tables 1-3:

TABLE 1 Exemplary anti-peripheral neuropathic compounds of the inventionare shown in Tables 1 and 2 below:

TABLE 2

1,4-Pentanediamine,N4-[7-chloro-2-[(1E)-2-(2-chlorophenyl)ethenyl]-4-quinolinyl]-N1,N1- diethyl-

1,4-Pentanediamine,N4-[7-chloro-2-[2-(2-chlorophenyl)ethenyl]-4-quinolinyl]-N1,N1- diethyl-

1,4-Pentanediamine,N4-[7-chloro-2-[2-(2,6-dichlorophenyl)ethenyl]-4-quinolinyl]-N1,N1- diethyl-

TABLE 3 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline(chloroquine); 7-hydroxy-4-(4-diethylamino-1-methylbutylamino)quinoline;chloroquine phosphate; 7-chloro-4-(4-diethylamino-1-butylamino)quinoline(desmethylchloroquine);7-hydroxy-4-(4-diethylamino-1-butylamino)quinoline;7-chloro-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;7-hydroxy-4-(1-carboxy-4-diethylamino-1-butylamino)quinoline;7-chloro-4-(1-carboxy-4-diethylamino-1-methylbutylamino)quinoline;7-hydroxy-4-(1-carboxy-4-diethylamino-1-methylbutylamino) quinoline;7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino) quinoline(hydroxychloroquine);7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-methylbutyl amino)quinoline; hydroxychloroquine phosphate;7-chloro-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline(desmethylhydroxychloroquine);7-hydroxy-4-(4-ethyl-(2-hydroxyethyl)-amino-1-butylamino) quinoline;7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline; 7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-butylamino)quinoline;7-chloro-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;7-hydroxy-4-(1-carboxy-4-ethyl-(2-hydroxyethyl)-amino-1-methylbutylamino)quinoline;8-[(4-aminopentyl)amino]-6-methoxydihydrochloride quinoline;1-acetyl-1,2,3,4-tetrahydroquinoline; 8-[4-aminopentyl)amino]-6-methoxyquinoline dihydrochloride;1-butyryl-1,2,3,4-tetrahydroquinoline;7-chloro-2-(o-chlorostyryl)-4-[4-diethylamino-1-methylbutyl]aminoquiinoline phosphate;3-chloro-4-(4-hydroxy-α,α′-bis(2-methyl-1-pyrrolidinyl)-2,5-xylidinoquinoline, 4-[(4-diethylamino)-1-methylbutyl)amino]-6-methoxyquinoline; 3,4-dihydro-1(2H)-quinolinecarboxyaldehyde; 1,1′-pentamethylenediquinoleiniumdiiodide; 8-quinolinol sulfate; Chloroquine 4-acetaminosalicylate;Chlorquinaldol; 3-Methylchloroquine;3-Carboxy-4-hydroxy-7-chloroquinoline; 4,7-Dichloroquinoline;7-Chloro-4-hydroxyquinoline; 6-Chloroquinaldine;N,2,6-Trichloro-4-benzoquinone imine; Hydroxychloroquine; Chloranil;Clioquinol; Cloxyquin; Chloroquine sulfate; 8-Chloroquinoline;4-Chloroquinoline; 3-Chloroquinoline; 6-Chloroquinoline;2-Chloroquinoline; 2-Chloro-1,4-hydroxyquinone; 5-Chloroquinoline;2-Chloro-1,4-benzoquinone; 2,6-Dichlorobenzoquinone; Hydroxychloroquinesulfate; Chloroxine; 7-Chloroquinolin-8-ol; Chloroquinine phosphate;2-Chloroquinoxaline; Desethylchloroquine;2,3-Dichloroquinoxaline-6-carbonylchloride; 2,3-Dichloroquinoxaline;2-Chloroquinoline-4-carbonyl chloride; 4,11-Dichloroquinacridonequinone;2,9-Dichloroquino(2,3-b)acridine-6,7,13,14(5H,12H)-tetrone;2,3,6-Trichloroquinoxaline; Chlorquinox; Chloroquine hydrochloride;Glafenine; Chloroquine mustard; N,N-Dideethylchloroquine; Cletoquine;Chloroquine-ethyl phenyl mustard; 4-Chloroquinazoline;4-(3′,5′-Bis(pyrrolidinomethyl)-4-hydroxyanilino)-7-chloroquinoline;6-Chloroquinoxaline; 6-Chloro-8-aminoquinoline;2-Chloromethyl-4-phenyl-6-chloroquinazoline-3-oxide;2-Chloroquinazoline; 4-(2-Methyl-1-pyrrolidyl)-7-chloroquinoline;6,7-Dichloroquinoline-5,8-dione; 6,7-Dichloroquinoxaline-2,3-dione;Cloquinate; 8-Quinolinol, 7-bromo-5-chloro-; Collagenan;Dichlorquinazine; 4,7-Dichloroquinolinium tribromide; Chloroquinoline;Chloroquine diorotate; 2,4,6-Triamino-5-chloroquinazoline;Methyl-8-(5,7-dichloroquinolyl)carbonic acid ester;6-Amino-7-chloro-5,8-dioxoquinoline; 4,8-Dichloroquinoline;5-Chloroquinolin-8-ol hydrochloride;3-Phenyl-4-hydroxy-7-chloroquinolin-2(1H)-one;N-Methyl-6-chloroquinolinium iodide; 3-Chloroquinuclidine hydrochloride;Halacrinate; 1-Phenacyloxime-4,5-dichloroquinolinium chloride hydrate;Chloroquine diascorbate; 2-(7-Chloroquinolin-4-yl)anthranilic acidhydrochloride; Tripiperaquine;2-(2-Chlorostyryl)-4-(delta-diethylamino-alpha-methylbutylamino)-7-chloroquinazoline; (+)-Chloroquine; (−)-Chloroquine;7-Chloro-4-(3-octylaminopropyl)aminoquinoline 1-oxide; Ethyl chloroquinemustard; L-Chloroquine; 2,6-Dianilino-6-chloroquinoxaline;2-(2-(5-Nitrofuryl)vinyl)-4-(delta-diethylamino-alpha-methylbutylamino)-7-chloroquinazoline; D-Chloroquine;2,3-Bis(allylamino)-6-chloroquinoxaline; 7-Chloroquinolin-4-olhydrochloride; 2-Amino-3,4-dichloroquinoline; Quizalofop; Presocyl;Tris(5,7-dichloroquinolin-8-olato-N1,O8)aluminium; Contramibial;Quinclorac; N-(4((7-Chloroquinolin-4-yl)amino)pentyl)-N-ethylacetamide;7-Bromo-5-chloroquinolin-ol; Chlorsulfaquinoxaline;1-Dimethylaminopropyl-3-methyl-6-chloroquinoxaline-2(1H)-one;Propaquizafop; 3-Chloroquinoline-8-carboxylic acid;5,10,15,20-Tetraphenyl-1-3-(4-(4-aminobutyl)-7-chloroquinoline)propioamidoporphine;4-((Carboxymethyl)amino)-5,7-dichloroquinoline-2-carboxylic acid;4-((Carboxymethyl)oxy)-5,7-dichloroquinoline-2-carboxylic acid;5,7-Dichlorokynurenic acid;N1,N2-Bis(7-chloroquinolin-4-yl)cyclohexane-1,2-diamine; Meclinertant;5-(2-(1-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)benzyl)indol-7-yl)ethyl)-1H-tetrazole;(N1-(7-Chloroquinolin-4-yl)-3-(N3,N3-diethylamino)propylamine)dihydrochloride trihydrate; and enantiomers thereof, and mixturesthereof, and suitable pharmaceutical salts thereof.

Another aspect of the invention is directed toward methods of treatingor preventing neuropathy in a subject including administering to thesubject a modulator of glial cell-derived neurotrophic factor (GDNF)receptor.

In certain embodiments, the modulator may be an agonist of the GDNFreceptor GFRα1 and/or GFRα2. The agonist may be a non-peptidyl agonist,particularly is X1134035.

A further aspect of the present invention is directed toward topicallotions including a subject anti-peripheral neuropathic quinolinecompound, or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable carrier formulated for topical application.

In another aspect, the present invention provides “pharmaceuticallyacceptable” compositions, that include a therapeutically effectiveamount of one or more of the compounds described herein, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. The pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for topical application,for example, as a cream, ointment, drops, gels, or a controlled-releasepatch or spray or sustained-release formulation applied to the skin, forexample, as a cream or foam.

Certain aspects of the invention include topical lotion formulations. Atopical lotion comprises a therapeutically effective amount of one ormore of the compounds described herein and a topical carrier. Topicalcarriers include but are not limited to creams, ointments, drops, gels,or a controlled-release patch or spray or sustained-release formulationapplied to the skin. Suitable carrier components include, but are notlimited to, mineral oil, sorbitan monostearate, polysorbate 60, cetylesters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, liquidpetroleum, white petroleum, propylene glycol, polyoxyethylenepolyoxypropylene compound, emulsifying wax and water.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose materials, compositions, and/or dosage forms which are, within thescope of sound medical judgment, suitable for use in contact with thetissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, or solvent encapsulatingmaterial, involved in carrying or transporting the subject extract fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; alginic acid;sterile distilled water; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; pH buffered solutions; polyesters,polycarbonates and/or polyanhydrides; and other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, and perfuming agents, preservatives andantioxidants can also be present in the compositions.

The compounds of the present invention can be administered orally,parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation, byinhalation, or by application to mucous membranes, such as, that of thenose, throat, and bronchial tubes. They may be administered alone orwith suitable pharmaceutical carriers, and can be in solid or liquidform such as, tablets, capsules, powders, solutions, suspensions, oremulsions.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent, or with an assimilableedible carrier, or they may be enclosed in hard or soft shell capsules,or they may be compressed into tablets, or they may be incorporateddirectly with the food of the diet. For oral therapeutic administration,these active compounds may be incorporated with excipients and used inthe form of tablets, capsules, elixirs, suspensions, syrups, and thelike. Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage of the compound in these compositionsmay, of course, be varied and may conveniently be between about 2% toabout 60% of the weight of the unit. The amount of active compound insuch therapeutically useful compositions is such that a suitable dosagewill be obtained. Preferred compositions according to the presentinvention are prepared so that an oral dosage unit contains betweenabout 1 and 250 mg of active compound.

The tablets, capsules, and the like may also contain a binder such asgum tragacanth, acacia, corn starch, or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid; a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose, or saccharin. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier, such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar, or both. A syrup may contain, in addition to activeingredient, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye, and flavoring such as cherry or orange flavor.

These active compounds may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant, such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Illustrative oils are those ofpetroleum, animal, vegetable, or synthetic origin, for example, peanutoil, soybean oil, or mineral oil. In general, water, saline, aqueousdextrose and related sugar solution, and glycols such as, propyleneglycol or polyethylene glycol, are preferred liquid carriers,particularly for injectable solutions. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms, such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds of the present invention may also be administered directlyto the airways in the form of an aerosol. For use as aerosols, thecompounds of the present invention in solution or suspension may bepackaged in a pressurized aerosol container together with suitablepropellants, for example, hydrocarbon propellants like propane, butane,or isobutane with conventional adjuvants. The materials of the presentinvention also may be administered in a non-pressurized form such as ina nebulizer or atomizer.

The compounds of the present invention may also be administered directlyto the airways in the form of a dry powder. For use as a dry powder, thecompounds of the present invention may be administered by use of aninhaler. Exemplary inhalers include metered dose inhalers and drypowdered inhalers. A metered dose inhaler or “MDI” is a pressureresistant canister or container filled with a product such as apharmaceutical composition dissolved in a liquefied propellant ormicronized particles suspended in a liquefied propellant. The correctdosage of the composition is delivered to the patient. A dry powderinhaler is a system operable with a source of pressurized air to producedry powder particles of a pharmaceutical composition that is compactedinto a very small volume. For inhalation, the system has a plurality ofchambers or blisters each containing a single dose of the pharmaceuticalcomposition and a select element for releasing a single dose.

Suitable powder compositions include, by way of illustration, powderedpreparations of the active ingredients thoroughly intermixed withlactose or other inert powders acceptable for intrabronchialadministration. The powder compositions can be administered via anaerosol dispenser or encased in a breakable capsule which may beinserted by the patient into a device that punctures the capsule andblows the powder out in a steady stream suitable for inhalation. Thecompositions can include propellants, surfactants, and co-solvents andmay be filled into conventional aerosol containers that are closed by asuitable metering valve.

EXAMPLES

First we used a transgenic mouse line (GFAP-DN-erbB4) in which erbBreceptor function in non-myelinating cells (NMSCs) is eliminated byexpression of a dominant negative erbB receptor (6). Around 21 days ofage, these mice begin to show symptoms of SFN, including loss of thermalnociception, breakdown of Remak bundles (unmyelinated axons surroundedby a NMSC), degeneration of c-fibers and death of NMSCs. Thisdegenerative process coincides with dramatic reduction in the levels ofGDNF expression in peripheral nerves, suggesting that loss of GDNF couldbe implicated in the pathogenesis of SFN (6) in this model.

As a first test of the effects of target-derived trophic support viaGDNF receptor activation in this model we crossed GFAP-DN-erbB4 micewith a previously characterized mouse line that over-expresses GDNF inthe skin under the control of the keratin 14 promoter (K14-GDNF) (8). Inthese mice GDNF expression in the skin is ˜6-fold higher than that foundin wild type skin and leads to increased numbers of sensory terminals(8), indicating that the transgenic GDNF is active and has an impact onsensory neurons. Importantly, despite this hyper-innervation, K14-GDNFmice have normal sensory behavior and are otherwise normal (8),indicating that GDNF over-expression in the skin has no deleteriouseffects.

GFAP-DN-erbB4 and K14-GDNF double and single transgenic mice were testedfor sensory function using a hot plate test. As shown previously, adult(6-week-old) K14-GDNF mice responded normally in this assay (8) whileGFAP-DN-erbB4 mice had a dramatic loss in thermal-nociception and neededto be removed from the hot plate after 30 seconds (6). In contrast,withdrawal latencies in GFAP-DN-erbB4::K14-GDNF double transgenic micewere indistinguishable from those of wild types, indicating that thesensory deficit in GFAP-DN-erbB4 mice was rescued by over-expression ofGDNF in the skin.

In our previous characterization of GFAP-DN-erbB4 mice we showed thatloss of thermal nociception correlates with dramatic alterations inperipheral nerve structure, including disruption of Remak bundles (6).Therefore, we used electron microscopy to examine Remak bundle structurein mice of the four genotypes. Remarkably, GFAP-DN-erbB4::K14-GDNFdouble transgenic mice contained many normal-appearing Remak bundles.Since the ability of mice to respond to noxious thermal stimuli dependson c-fiber sensory terminals in the footpads and patients withsymptomatic SFN have reduced epidermal nerve fiber density (10), wetested whether these terminals were disrupted in GFAP-DN-erbB4 mice, andif so, can they be rescued by GDNF over-expression. Quantification offree nerve endings identified by expression of the neuronal markerprotein gene product 9.5 (PGP9.5) at P30 confirmed previous reports ofhyper-innervation in the skin of K14-GDNF mice compared to wild typeskin (8), while GFAP-DN-erbB4 mice showed reduced nerve terminals in theskin at this age. Consistent with the rescue of thermal nociception indouble transgenic mice, we observed preservation of nerve terminals inthe skin of GFAP-DN-erbB4::K14-GDNF mice compared to GFAP-DN-erbB4 mice.Over-expression of GDNF not only improved the axonal phenotyes ofGFAP-DN-erbB4 mice but also reduced the extent of Schwann cell death,indicating that trophic support delivered at the target of innervationpreserves the health of glial cells along the nerve. Importantly, levelsof DN-erbB4 expression in sciatic nerves of double transgenic mice weresimilar to those in GFAP-DN-erbB4 mice, indicating that reversion of theSFN in double transgenic mice was not due to an effect of GDNF onDN-erbB4 expression. These results show that GDNF over-expression in theskin also rescues the anatomical phenotypes along the nerve produced byDN-erbB4 expression in NMSCs.

The results described above suggest that GDNF over-expression in theskin could be used to treat progressive SFNs like the one found inGFAP-DN-erbB4 mice. However, since K14-GDNF mice overexpress this factorfrom embryonic development, the possibility that alterations indevelopment could have contributed to the phenotypic rescue could not beoverlooked. Furthermore, when considering treatment of humans, GDNFover-expression would require some type of gene therapy, which has itsown drawbacks and complications. Thus, we felt it was necessary to testalternative approaches to activate GDNF signaling in the skin as atreatment for SFN. Since proteins such as GDNF do not readily diffusethrough the skin, we tested if XIB4035, a non-peptidyl small moleculeagonist for the GDNF receptor GFRα1 (11) would be a useful alternative.XIB4035 had previously been shown to activate the Ret co-receptor bybinding to the GFR 1 GDNF receptor in both human and murine cells (11).

We generated a cream containing XIB4035 (1.2 mM) and applied it directlyto the hind paws of GFAP-DN-erbB4 and wild type mice twice daily for aperiod of 4 weeks starting at the time of weaning (P21). Importantly, bythis age GFAP-DN-erbB4 mice already exhibit neuropathic symptoms (6).Thus, these experiments would test whether activation of Ret signalinghas therapeutic effects after disease onset. To control for potentialeffects of the control cream, mice of both genotypes were treated in thesame way with the base cream without the drug. Mice were tested forresponses to noxious thermal stimulus prior to the initiation oftreatment and every 7 days throughout the treatment period. Over the 4week treatment period, the behavior of wild type mice remained normal,independent of the presence of XIB4035 in the cream while GFAP-DN-erbB4mice treated with control cream progressively lost thermal nociceptionas we found in untreated animals (6). In contrast, when treated withcream containing XIB4035, GFAP-DN-erbB4 mice showed dramaticpreservation of thermal nociception, their behavior being similar tothat of wild type mice. As expected from our previous characterizationof GFAP-DN-erbB4 mice (6), response thresholds to punctate mechanicalstimuli remained normal in all groups after the 4 weeks of treatment,indicating that the drug had no effect on mechanoreception. Together,these findings indicate that topical treatment with XIB4035 preservesthe ability of mice with SFN to respond to noxious heat stimulus withoutinducing hypersensitivity. They also show that treatment of unaffectedmice with XIB4035 had no deleterious effects on their ability to respondto heat or mechanical stimuli.

From the anatomical point of view, similarly to what we found in thedouble transgenic mice, 4-week treatment with XIB4035 prevented thedegeneration of Remak bundles and c-fiber axons. Morphometric analysisshowed that XIB4035 treatment preserved both the size of c-fiber axonsand the number of c-fibers per Remak bundle in GFAP-DN-erbB4 mice.Furthermore, NMSC apoptosis was also significantly reduced inGFAP-DN-erbB4 mice treated with XIB4035. Interestingly, like GDNFover-expression, drug treatment not only prevented degeneration ofsensory nerve terminals in the footpad skin of GFAP-DN-erbB4 mice, butit increased the density of nerve terminals in wild type skin.

As it is unlikely that SFN is always caused by glial dysfunction, weconsidered it necessary to test the effectiveness of XIB4035 treatmenton SFN resulting from a different pathogenic mechanism. Therefore wetested the efficacy of our therapeutic approach in resiniferatoxin(RTX)-induced SFN (9). RTX-induced SFN involves intraperitonealinjection of an ultrapotent capsaicin analog that targets c-fiberterminals by binding to and activating TRPV1 channels resulting incalcium influx, which induces loss of skin innervation and loss ofthermal nociception (9). After RTX injection, mice were either treatedimmediately with XIB4035 or treatment was delayed by 12 hours. Bothtreatment paradigms yielded similar results.

Similar to the effect seen in GFAP-DN-erbB4 mice, treatment with XIB4035greatly improved thermal nociception in the RTX model. Seven days afterRTX treatment paw withdrawal latencies were greatly increased in animalstreated with control cream. In contrast, RTX-injected animals that weretreated with XIB4035 had remarkable preservation of their ability torespond to noxious heat. Furthermore, innervation of the skin waspreserved as a result of XIB4035 treatment in RTX-injected mice. Asexpected based on the preservation of thermal nociception and skininnervation, Remak bundle structure was also significantly improved inRTX-injected animals treated with XIB4035. Both c-fiber area and thenumber of fibers per Remak bundle were improved by treatment withXIB4035 in RTX-induced SFN.

Together, these results indicate that SFNs may be treated by supplyingligands for neurotrophic factor receptors at the target of innervation,providing an alternative to invasive or systemic routes of delivery.Using either “gene therapy” or a “topical” pharmacological approach weshow that application of GDNF receptor ligands to the skin results inpreservation of nerve structure and function in two mouse models of SFN.Since SFN occurs frequently as a late-onset complication of a number ofdiseases, e.g. diabetes, topical application of GDNF receptor ligandscan be considered as a preventive therapy after the first diseasesymptoms, e.g. hyperglycemia, appear. Nevertheless, since topicalapplication of the drug to mice was effective after the onset of sensorydefects, our studies indicate that this type of treatment could helpeven after patients develop SFN symptoms.

The results presented herein together with our previous analysis ofGFAP-DN-erbB4 mice (6) also provide insights into the roles of trophicfactors in adult nerves. The emerging picture is that GDNF produced bySchwann cells along the nerve is necessary for the maintenance ofc-fiber structure and function, and that endogenous GDNF can be replacedby application of GDNF or synthetic ligands to the sensory nerveendings. If similar mechanisms are at work in other nerves, this type oftherapeutic intervention could be used to treat other neuropathies,including those involving central nerves, i.e. optic nerve. Furthermore,the use of this type of drug to treat degenerative processes involvingother neurons that express receptors for the GDNF family, e.g. spinalcord motorneurons, using intramuscular injections, should be considered.Furthermore, these results demonstrate that tyrosine kinase signaling incells or cell segments within the skin can be modified by the topicalapplication of a non-peptidyl molecule. Therefore, in addition to theresults presented herein, this strategy might also be useful to locallytreat other disorders such as skin cancer (12, 13).

Previous animal tests of the effectiveness of systemic or intrathecalinjection of neurotrophic factors as therapeutic agents for peripheralneuropathy have provided encouraging results (14-16). However, humantrials using injections of trophic factors to treat peripheralneuropathies have either resulted in severe side effects or have beenineffective altogether. For example, trials examining the efficacy ofNGF treatment in diabetic patients with peripheral neuropathy orpatients with HIV neuropathy have shown some improvement in thepatient's perception of symptom severity, but side effects includingmyalgia, peripheral edema, and hyperalgesia were also observed (17-19).Test of GDNF injections for other neurological disorders have beenmarred by serious side effects. For example, intracerebroventricularadministration of GDNF results in weight loss, anorexia, and nauseawhile providing little benefit to Parkinson's disease patients (20). Ourresults indicate that topical treatment with small molecule agonists forneurotrophic factor receptors, e.g. GDNF receptor ligands, can providean effective treatment for peripheral neuropathies without the sideeffects associated with generalized delivery.

Animals and Induction of Neuropathy Using RTX.

Transgenic mouse lines used were as previously described (6, 8). Animalswere kept in the animal facility with free access to food and water.Behavioral experiments were performed in a quiet environment at the sametime of day. The hot plate test was performed using a “controlledhot-plate analgesia meter” (Columbus Instruments) heated to 55° C. Pawwithdrawal latency was measured as the time required for the mouse tovisibly respond to the thermal stimulus, e.g. licking paws, liftingpaws, or jumping off of the plate. Mechanical sensitivity was tested bysimulation of the plantar surface of the hind paw with a series of vonFrey filaments while the animal was placed on an elevated wire grid. Thethreshold was determined as the lowest force that evoked a visiblewithdrawal response. 8-week-old ICR mice weighing at least 30 g wereinjected intraperitoneally with RTX (50 mg/kg) or vehicle (10% Tween-80,10% ethanol in isotonic saline) (9).

Preparation and Use of XIB4035.

The cream containing XIB4035 (1.2 mM, Matrix Scientific, Columbia, S.C.)consisted of N-methyl-pyrrolidone (5%), isopropyl myristate (5%) andpetroleum jelly (90%). Control cream had the same ingredients withoutXIB4035. Cream was applied twice daily to the hind paws of isofluraneanesthetized mice starting at P21 for a period of 9 days (for analysisof cell death in sciatic nerves) or 4 weeks (all other studies usingGFAP-DN-erbB4). Treatment of RTX-induced neuropathy began at the time ofRTX injection or 12 hours after RTX injection and proceeded twice dailyfor a period of one week.

Plastic Embedding and Electron Microscopy.

Tissue was prepared as in (6). Briefly, mice were perfusedintracardially with 2% paraformaldehyde, 2.5% gluteraldehyde and 0.03%picric acid in 0.1 M cacodylate buffer (pH 7.2). Tissue was post-fixedovernight at 4° C. and embedded in Epon. Ultrathin sections were cut,collected on cellodin-coated grids and stained using uranyl acetate andlead citrate. Photographs were taken using the Tecnai G² Spirit BioTWINtransmission electron microscope.

Immunohistochemistry.

Mice were anesthetized with 2.5% Avertin and footpad skin was removedand immersion fixed in 4% paraformaldehyde, 14% picric acid in 0.1 Mphosphate buffer (pH 7.3) overnight at 4° C. and cryoprotected in 20%sucrose overnight at 4° C. Tissues were embedded in OCT and sectioned at30 m and stained as floating sections by washing 3 times for 5 minutesin PBS+0.1% Triton-X 100, blocked for 30 minutes in PBS+0.1% Triton-X100+10% normal goat serum and then incubated, PGP9.5 rabbit polyclonalantibody (Ultraclone, 1:1000), overnight at 4° C. Sections were washed 3times for 10 minutes in PBS+0.1% Triton-X 100 then incubated in donkeyanti-rabbit Alexa-488 (Invitrogen) 1:300 for 2 hours at roomtemperature. Nuclei were stained with DAPI and sections were mountedwith Gel-Mount.

Cell Death Detection.

Sciatic nerves were dissected from mice perfused with 4%paraformaldehyde in PBS and fixed overnight at 4° C. Nerves wereembedded in OCT and 16 m thick transverse sections were processed forTUNEL as follows. Sections were washed 3 times for 5 minutes with PBSfollowed by proteinase K digestion (0.02 U/mL) in 10 mM TRIS/HCl pH 7.5for 30 minutes at 37° C. Digested sections were fixed with 4%paraformaldehyde at room temperature for 20 minutes followed by 3 washesin PBS for 5 minutes. Apoptotic nuclei were identified using the In SituCell Death Detection Kit (Roche). Nuclei were stained with DAPI andsections were mounted with Gel-Mount.

REFERENCES

-   1. N. R. Holland et al., Ann Neurol 44, 47 (July, 1998).-   2. D. Lacomis, Muscle Nerve 26, 173 (August, 2002).-   3. D. R. Cornblath, A. Hoke, Curr Opin Neurol 19, 446 (October,    2006).-   4. W. Luo et al., Neuron 54, 739 (Jun. 7, 2007).-   5. D. C. Molliver et al., Neuron 19, 849 (October, 1997).-   6. S. Chen et al., Nat Neurosci 6, 1186 (November, 2003).-   7. R. Hellweg, G. Raivich, H. D. Hartung, C. Hock, G. W. Kreutzberg,    Exp Neurol 130, 24 (November, 1994).-   8. M. Zwick et al., J Neurosci 22, 4057 (May 15, 2002).-   9. Y. L. Hsieh, H. Chiang, T. J. Tseng, S. T. Hsieh, J Neuropathol    Exp Neurol 67, 93 (February, 2008).-   10. N. R. Holland et al., Neurology 48, 708 (March, 1997).-   11. K. Tokugawa et al., Neurochem Int 42, 81 (January, 2003).-   12. D. J. Easty, D. C. Bennett, Melanoma Res 10, 401 (October,    2000).-   13. F. J. Lejeune, D. Rimoldi, D. Speiser, Expert Rev Anticancer    Ther 7, 701 (May, 2007).-   14. D. L. Bennett et al., J Neurosci 18, 3059 (Apr. 15, 1998).-   15. D. Perrelet et al., Nat Cell Biol 4, 175 (February, 2002).-   16. Q. Yan, J. Wang, C. R. Matheson, J. L. Urich, J Neurobiol 38,    382 (Feb. 15, 1999).-   17. S. C. Apfel et al., Neurology 51, 695 (September, 1998).-   18. J. C. McArthur et al., Neurology 54, 1080 (Mar. 14, 2000).-   19. G. Schifitto et al., Neurology 57, 1313 (Oct. 9, 2001).-   20. J. G. Nutt et al., Neurology 60, 69 (Jan. 14, 2003).

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow. All references cited herein, and referencescited therein are incorporated by reference as if each was specificallyand individually indicated to be incorporated by reference.

1-20. (canceled)
 21. A method of treating or preventing a small fiberperipheral neuropathy in a subject determined to be in need thereofcomprising: administering to the subjectN⁴-{7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl}-N¹,N¹-diethyl-pentane-1,4-diamine(XIB4035) or a pharmaceutically acceptable salt thereof under conditionseffective to treat or prevent the peripheral neuropathy in the subject.22. The method of claim 21, wherein the XIB4035 is administered orally.23. The method of claim 21, wherein the XIB4035 is administeredparenterally.
 24. The method of claim 21, wherein the XIB4035 isadministered by injection.
 25. The method of claim 21, wherein theXIB4035 is administered by a route selected from the group consisting ofsubcutaneously, intravenously, intramuscularly, intraperitoneally, byintranasal instillation, by inhalation and by application to mucousmembranes
 26. The method of claim 21, wherein the XIB4035 is applied toa mucous membrane selected from the group consisting of that of thenose, throat and bronchial tube.
 27. The method of claim 21, wherein theXIB4035 delivers systemically.
 28. The method of claim 21, whereinbetween 1 and 250 mg of XIB4035 is administered to the subject in asingle dose.
 29. The method of claim 21, wherein the subject is human.30. The method of claim 21, further comprising the antecedent step ofdetermining that the subject is in need of said method by detecting thesmall fiber neuropathy in the subject.
 31. The method of claim 21,further comprising the subsequent step of detecting a resultantdiminution of the small fiber neuropathy.
 32. A formulation comprisingN⁴-{7-chloro-2-[(E)-2-(2-chloro-phenyl)-vinyl]-quinolin-4-yl}-N¹,N¹-diethyl-pentane-1,4-diamine(XIB4035) or a pharmaceutically acceptable salt thereof in an amounteffective to treat or prevent a peripheral neuropathy in a subject, anda pharmaceutically acceptable carrier formulated for administration. 33.The formulation of claim 32, wherein the formulation contains betweenabout 1 to 250 mg of XIB4035.
 34. The formulation of claim 32, whereinthe formulation comprises a dosage of XIB4035 effective for treatment ofperipheral neuropathy in the subject.
 35. The formulation of claim 32,formulated for parenteral administration.
 36. The formulation of claim32, formulated for injection.
 37. The formulation of claim 32,formulated for oral administration.
 38. The formulation of claim 32,formulated as a tablet.
 39. The formulation of claim 32, formulated forinhalation.
 40. The formulation of claim 32, wherein XIB4035 is presentat about 2% to about 60% of the weight of the formulation.